AB0119 ROLE OF COSTIMULATORY MOLECULES IN SYSTEMIC LUPUS ERYTHEMATOSUS: FOCUS ON CD137
Authors: F. Natalucci, A. Di Filippo, F. Ceccarelli, I. Zizzari, G. Olivieri, V. Orefice, C. Pirone, F. R. Spinelli, C. Alessandri, M. Nuti, F. Conti
Journal: Annals of the Rheumatic Diseases (2022)

Background Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by a wide autoantibodies production. The traditionally concept of a B-cell driven disease has been changed in the last years due to the evidence demonstrating the crucial role of T cells in SLE pathogenesis. In particular, regulatory (Treg) and memory T cells seem act through co-stimulatory and co-inhibitory molecules, such as CD137, PD1-1 and CTLA4. The over-expression of this molecules on lymphocytes may contribute to immune system dysregulation. Objectives The primary objective of the present case-control study was to evaluate the expression of CD137, PD1-1 and CTLA4 on T cell surface of SLE patients by using flow-cytometry. Secondly, we evaluated the percentage of Treg and memory T cells. Methods We enrolled patients SLE patients (2019 ACR/EULAR criteria) and sex/age-matched healthy subjects (HS). Demographic, clinical, and laboratory data were collected in a standardized computerized electronically filled form. Disease activity was assessed by SLEDAI-2k. Each subject underwent peripheral blood sample collection. By using flow-cytometry we evaluated the expression of FOXP3, CD137, PD1-1 and CTLA4, CD45, CD25, CCR7 to determine the percentage of Treg and memory T cells. Results The present analysis included 21 SLE patients [M/F 1/20 median age 48 years (IQR 17), median disease duration 144 months (IQR 204)]. The Treg percentage was significantly lower in SLE compared to HS [median 4.2 (IQR 0.32) versus 2.5 (IQR 2.44); p=0.001, Figure 1A]. Moving on effector Treg (eTreg), SLE patients with high disease activity (SLEDAI &gt; 4) showed a significantly higher prevalence for these cells compared to patients with SLEDAI ≤ 4 [1.16 (IQR 0.51) versus 0.53 (IQR 0.8), p=0.014, Figure 1B]. Moreover, inverse correlation was found between eTreg percentage and SLEDAI-2k [p=0.029, r=-0.47 (CI 0.75 – 0.04) Figure 1C]. The evaluation of CD137 expression was significantly higher in SLE patients compared to HS on CD3+ cells [median 5.32 (IQR 6.11) versus 3.3 (IQR 1.7), p=0.001, Figure 1F]. On CD4+ cells, CD137 expression positively correlated with disease activity [p=0.0082, r=0.58 (CI 0.15-0.82)]. Finally, when analysing memory T cells subpopulations, inverse correlation has been found between effector memory T cells (TEM, CD45RA-CCR7-) and SLEDAI-2k when considering CD3+ [p=0.029, r=-0.56 (CI 0.81 – 0.12)] and CD4+ cells [p=0.016, R=-0.54 (CI -0.80 - -0.1)]. Of note, CD137 expression on T central memory cells (TCM, CD45RA-CCR7+) positively correlated with SLEDAI-2k [(p=0.019, r=0.52 (CI 0.09 – 0.79)]. Figure 1. A) Comparison of the percentage of Treg in HS and SLE patients. B) Comparison of the percentage of eTreg in SLE patients with high disease activity and low disease activity C) Correlation between % eTreg and SLEDAI-2k. D) Comparison of the percentage of CD3+CD137+ cells in HS and SLE patients. E) Comparison of % of CD4+CD137+ cells in SLE patients with high disease activity and low disease activity F) Correlation between % of CD4+CD137+ cells and SLEDAI-2k. Conclusion Our results suggest a possible role of CD137-CD137L axis in SLE pathogenesis. The stimulatory role of this molecule is indicated by the positive correlation between SLEDAI-2k values and surface expression of CD137. Moreover, inverse correlation between SLEDAI-2k and eTreg percentage suggests a possible Treg dysregulation in SLE. Table 1. SLE cohort features Clinical and Laboratory Features Mucocutaneous 80.9% Articular 76.1% Serositis 19.0% Kidney 23.8% Haematological 48.2% CNS/PNS 9.5% Thrombotic events 4.7% anti-dsDNA 68.4% anti-SSA/anti-SSB 47.6% anti-RNP 19.0% anti-Sm 33.0% Antiphospholipid antibodies 14.2% Low C3/C4 57.1% Previous Therapy Glucocorticoid 90.5% Hydroxychloroquine 95.2% Methotrexate 23.8% Mofetil Mycophenolate 33.3% Ciclosporin 28.5% Cyclophosphamide 9.5% Azathioprine 33.3% Rituximab 14.3% Antiplatelet 23.8% Anticoagulant therapy 4.7% Disclosure of Interests None declared